Receptor-ligand based imaging systems are being used as tools for identifying aberrant cellular growth and altered cellular phenotypes in mouse models and in humans. Despite several advantages; e.g., high affinity interactions of receptor with ligand, targeting endogenous receptors has inherent difficulties, such as, up-take of toxic ligands within non-targeted tissue(s). To circumvent some of these problems, while maintaining high specificity, we have developed a novel non-mammalian receptor-ligand (ER-1mem-ER-1) system to be used in optical, MR and PET imaging in animal models. We intend to combine the ER-1mem imaging system with the study of tumor hypoxia. The ER-1mem gene will be placed under the control of the hypoxia inducible promoter. Thus, the tracking ER-1mem receptor expression in solid tumors in living mice will facilitate our understanding of the spatial/temporal development of hypoxia in solid tumors. In addition, we have generated a chimeric gene referred to as TatVPR, which is based on well defined functional components of HIV proteins. This chimera juxtaposes Tat protein's trans-membrane penetration domain with VPR's potent pro-apoptotic inducing domain. Preliminary results indicate that TatVPR is a potent cellular death molecule that elicits a substantial bystander effect. In summary, the use of ER-1mem imaging system will help us to locate hypoxic pockets within the tumor environment while TatVPR expression will ablate tumor hypoxia and thus, increase the efficacy of chemo and radiation therapies. We now propose to examine in depth the sensitivity of the ER-1mem imaging system. We aim to study the efficacy of the system to detect cells overexpressing ER-1mem, by modifying the ligand for different detection systems like optical, MR and PET. We will combine ER-1mem system to understand and evaluate formation of hypoxic regions within the tumor environment. Finally, based on our observation that TatVPR is an effective inducer of cell death, we will fully characterize its potential to ablate tumor hypoxia, thus augmenting the efficacy of standard chemotherapeutic agents. These studies will yield new insights into imaging and tracking tumor hypoxia and further elucidate mechanisms to decrease tumor burden prior to adjuvant therapies.